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Neurochemical Effects of Environmental Chemicals: In Vitro and In Vivo Correlations on Second Messenger Pathways a
Author(s) -
KODAVANTI PRASADA RAO S.,
TILSON HUGH A.
Publication year - 2000
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.2000.tb06872.x
Subject(s) - second messenger system , in vivo , signal transduction , protein kinase c , chemistry , microbiology and biotechnology , in vitro , neurochemical , biochemistry , biophysics , biology , endocrinology
A bstract : Polychlorinated biphenyls (PCBs) are persistent, bioaccumulative, toxic, and widely distributed environmental chemicals. There is now both epidemiological and experimental evidence that PCBs cause cognitive deficits; however, the underlying cellular or molecular mechanism(s) is not known. We have hypothesized that altered signal transduction/second messenger homeostasis by PCBs may be associated with these effects since second messengers in signal transduction pathways, such as calcium, inositol phosphates (IP), and protein kinase C (PKC), play key roles in neuronal development and their function. In vitro studies using cerebellar granule neurons and isolated organelle preparations indicate that ortho ‐PCBs increase intracellular free Ca 2+ levels by inhibiting microsomal and mitochondrial Ca 2+ buffering and the Ca 2+ extrusion process. Ortho ‐PCBs also increase agonist‐stimulated IP accumulation and cause PKC translocation at low micromolar concentrations where no cytotoxicity is observed. On the other hand, non‐ ortho ‐PCBs are not effective in altering these events. Further SAR studies indicate that congeners with chlorine substitutions favoring non‐coplanarity are active in vitro , while congeners favoring coplanarity are relatively inactive. Subsequent in vivo studies have shown that repeated exposure to a PCB mixture, Aroclor 1254, increases PKC translocation and decreases Ca 2+ buffering in the brain, similar to in vitro studies. These changes in vivo are associated with elevated levels of non‐coplanar ortho ‐PCB congeners at levels equivalent to 40–50 μM in brain, the concentrations that significantly inhibited second messenger systems in neuronal cultures in vitro . Current research is focusing on PCB‐induced alterations in second messenger systems following developmental exposure.